PROJECT SUMMARY The growing popularity of electronic cigarette (e-cig) use among adolescents is a cause for public health and regulatory concern. Current use of e-cigs among adolescents has increased more than 10-fold from 2011 to 2014 (1.5% to 17%). Although an e-cig delivers lower levels of known toxins than a combustible cigarette, both deliver nicotine, potentially fostering cross-product use through dependence on nicotine. Research indicates that the majority of adolescents who use e-cigs also use combustible cigarettes (i.e., dual use). While concerns have been raised regarding the potential for e-cigs to erode decades of adolescent smoking control efforts by promoting the uptake and persistence of combustible cigarette smoking, existing data cannot fully justify or allay these concerns. Prospective, longitudinal studies are urgently needed to address four vital questions. One, do e-cigs act as a catalyst for regular combustible cigarette smoking for youth who may not have otherwise smoked and if so, why? Two, do e-cigs contribute to the persistence of regular combustible cigarette smoking, possibly by allowing adolescents to substitute e-cigs for combustible cigarettes in smoke-free situations? Three, which adolescents are most likely to progress to regular e-cig use and then to dual use? Four, are there subgroups of adolescents with unique longitudinal patterns of single use and dual use (e.g., adolescents who only use e-cigs, adolescents who only smoke cigarettes, duals users who vary in their pathway to dual use) and what are the characteristics of adolescents who have these patterns of use? We propose to address these critical gaps in the evidence base by following a prospective, longitudinal cohort of 2,000 adolescents from mid (age 14 years) to late adolescence (age 18 years), measuring e-cig use, cigarette smoking, and individual and environmental risk factors for use every 6 months (8 waves total). Outcomes include the odds of progression to regular use (combustible, e-cig, and dual), smoking persistence, and trajectories of use. The proposed approach will enable us to create a comprehensive model of the developmental relationship between e-cig use and combustible cigarette smoking among adolescents, to identify unique patterns of use, and to determine the factors that drive single and dual use. A greater understanding of e-cig use and its relationship to combustible cigarette smoking will be fundamental to inform evidenced-based public health efforts and e-cig regulatory actions to protect youth from nicotine dependence and from smoking.